This randomized phase III trial studies lenalidomide to see how well it works with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia. Lenalidomide may stop the growth of myelodysplastic syndrome by blocking blood flow to the cells. Colony stimulating factors, such as epoetin alfa, may increase the number of immune cells found in bone marrow or peripheral blood. It is not yet known whether lenalidomide is more effective with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia.

Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) to Treatment With Lenalidomide (Revlimid®) Alone and in Combination With Epoetin Alfa (Procrit®) in Subjects With Low- or Intermediate-1 Risk MDS and Symptomatic Anemia

MER defined as sustained transfusion independence in transfusion-dependent patients or a rise in hemoglobin > 2 g/dL in transfusion-independent patients with anemia for a minimum of 8 consecutive weeks [ Time Frame: At 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Time to MER [ Time Frame: From randomization to the documented date of MER, assessed up to 16 weeks ] [ Designated as safety issue: No ]

Time to MER will be compared between lenalidomide monotherapy and combined treatment of lenalidomide and epoetin alfa in MER responders, using a one-sided log-rank test at the significance level of 0.025.

Duration of MER defined as the time interval between the documented date of MER and the earliest date of resumption of RBC transfusions >= 2 units, a reduction in hemoglobin concentration >= 2 g/dL [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

Summarized by Kaplan-Meier method for patients who achieve MER by treatment arms.

Rate of MER [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]

The 90% confidence interval of the rate of MER to salvage combination therapy will be computed in patients who fail to achieve an MER with lenalidomide monotherapy and cross over to the combination therapy.

I. To compare the time to MER by treatment assignment. II. To evaluate the duration of MER by treatment assignment. III. To estimate the frequency of MER to salvage combination therapy in patients who fail to experience a MER with lenalidomide monotherapy.

IV. To evaluate and compare the frequency of minor erythroid response by treatment assignment.

V. To investigate the mechanism and target of lenalidomide action in patients with chromosome 5q31.1 deletion.

VI. To evaluate the frequency of cytogenetic response and progression, and the relationship between cytogenetic pattern and erythroid response.

VIII. To evaluate the relationship between erythroid response and laboratory correlates outlined below: pretreatment and on study endogenous erythropoietin level (Arm A); to evaluate the effect of cluster of differentiation (CD)45 isoform profile on lenalidomide enhancement of erythropoietin-induced signal transducer and activator of transcription 5A (STAT5) phosphorylation in CD71^Hi erythroid precursors and the relationship to erythroid response; to characterize molecular targets relevant to lenalidomide cytotoxicity in del5q31.1 cells; to evaluate the frequency of cryptic chromosome 5q31.1 deletions in patients with non-del5q31.1 MDS by array-based genomic scan, and to determine the relationship to hematologic response.

OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients with del 5q31.1 karyotype are assigned to Arm A.

In both arms, treatment repeats every 28 days for 4 courses. Patients who achieve a major erythroid response (MER) may continue treatment beyond 4 courses in the absence of disease progression, disease conversion to acute myeloid leukemia, or unacceptable toxicity. Patients in Arm A who fail to achieve MER or who achieve MER but relapse after 16 weeks of treatment with lenalidomide may crossover and receive treatment in Arm B.

After completion of study treatment, patients are followed up for 6 months.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

NOTE: Results of the bone marrow biopsy and aspirate as well as cytogenetics are mandatory to register subjects onto study, which are indispensable to determine International Prognostic Scoring System (IPSS) category needed for eligibility; please note that it is not necessary to wait for the week 16, week 32, or week bone marrow and cytogenetic results prior to starting the next cycle unless deemed necessary by the treating physician; one example of this exception can include if the subject shows signs of progression, such as increased peripheral blood blast percentage; at that juncture, the treating physician may prefer to await the results prior to starting a new cycle; if a cycle is started, and based on the bone marrow results it is felt by the treating physician that the subject should not continue on treatment, please be sure to note this information on the case report forms at end of treatment

Patient must have IPSS categories of low- or intermediate-1-risk disease; patients must have IPSS score determined by cytogenetic analysis prior to randomization; patients must have cytogenetic analysis done (to calculate IPSS); if the current bone marrow biopsy is a dry tap, patients with cytogenetic failure and < 10% marrow blasts will be eligible; subjects with cytogenetic failure must have previous cytogenetic results (fluorescence in situ hybridization [FISH] is not a substitute) within the last 6 months post last type of MDS treatment (in this case, not referring to growth factors as type of MDS treatment)

For non-transfusion dependent patients, a minimum of 2 pre-transfusion or un-transfused hemoglobin values are required

Applies only for patients without the deletion 5q 31.1; patients must have failed treatment with an erythropoietic growth factor, or have a low probability of response to rhu-erythropoietin; patients with low probability of response to rhu-erythropoietin or prior erythropoietin failures are defined as follows:

Patients must be off all non-transfusion therapy for MDS for 28 days prior to initiation of study treatment, including all types of growth factors; patients may receive hydrocortisone prophylactically to prevent transfusion reactions

Patients must have a serum erythropoietin level documented before randomization and =< 56 days before day 1 of study treatment; NOTE: hemoglobin must be < 9.5 g/dL at time that serum erythropoietin is drawn

Patients must not have documented iron deficiency; all patients must have documented marrow iron stores; if marrow iron stain is not available, the transferrin saturation must be > 20% or a serum ferritin > 100 ng/mL

Women must not be pregnant or breastfeeding; females of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; a female of childbearing potential (FCBP) is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months; FCBP must also agree to ongoing pregnancy testing)

Effective contraception must be used by patients participating in lenalidomide therapy, and all patients must agree to counseling by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure; females of childbearing potential (FCBP) must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide, during lenalidomide therapy, during dose interruptions, and for at least 28 days following discontinuation of lenalidomide therapy; females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed; males receiving lenalidomide must agree to use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy

Patients must not have prior therapy with lenalidomide

Patients must not have a diagnosis of uncontrolled seizure or uncontrolled hypertension

Prior thalidomide is allowed, however, patients must not have prior >= grade-3 allergic reactions to thalidomide

Patients must not have prior history of desquamating rash from thalidomide at time of study entry

Patients must not have clinically significant anemia resulting from iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding

Patients must not have used cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 8 weeks of randomization

Patients must not have prior history of malignancy other than MDS (except basal cell or squamous skin cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been confirmed free of disease for >= 3 years

Patients must not have any serious medical condition or any other unstable medical co-morbidity, or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study

Patients must not have a history of thrombo-embolic events within 3 years prior to study randomization

Patients must not have known human immunodeficiency virus (HIV)-1 seropositivity

Patients must not have a known allergic reaction to epoetin alfa (Procrit) or human serum albumin

Eligibility for crossover registration from Arm A (lenalidomide alone) to Arm B (lenalidomide and epoetin alfa):

Patients must have completed 16 weeks of monotherapy with lenalidomide

Patients must show failure to achieve MER (major erythroid response) or have achieved MER but relapsed on Arm A

Patients must not have a limiting unresolved grade 3 or greater toxicity from lenalidomide monotherapy or drug intolerance preventing continuation of lenalidomide treatment

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00843882